JP2007084555A - 治療薬としての修飾ペプチド - Google Patents
治療薬としての修飾ペプチド Download PDFInfo
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- JP2007084555A JP2007084555A JP2006288325A JP2006288325A JP2007084555A JP 2007084555 A JP2007084555 A JP 2007084555A JP 2006288325 A JP2006288325 A JP 2006288325A JP 2006288325 A JP2006288325 A JP 2006288325A JP 2007084555 A JP2007084555 A JP 2007084555A
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Abstract
【解決手段】a)対象とするタンパク質の活性を変化させる少なくとも1個のペプチドを選択し、そしてb)選択したペプチドの少なくとも1個のアミノ酸に共有結合されたFcドメインを含む薬理学的物質を調製する、ことを含む工程によって薬理学的活性な化合物を製造する。ビヒクルへの結合は、インビボで速やかに分解されるであろうペプチドの半減期を高める。好ましいビヒクルはFcドメインである。ペプチドは、好ましくはファージディスプレイ、大腸菌ディスプレイ、RNA−ペプチドスクリーニング、又は化学物質−ペプチドスクリーニングによって選択する。
【選択図】なし
Description
組換えタンパク質は最近出現してきた治療薬のクラスのひとつである。かかる組換え治療は、タンパク質の生成と化学修飾における進歩をもたらした。そのような修飾は、主としてタンパク質分解酵素への接触を遮断することにより、治療タンパク質を保護することができる。タンパク質の修飾はまた、治療タンパク質の安定性、循環時間及び生物活性を高めることもできる。タンパク質修飾と融合タンパク質を述べた総説論文が、参照してここに組み込まれる、Francis(1992)、成長因子への注目(Focus on Growth Factors)、3:4−10(Mediscript,London)である。
本発明は、ビヒクル(vehicle)との融合により、1つ又はそれ以上の生物学的に活性なペプチドのインビボ半減期を延長させる方法に関する。本発明では、薬理学的に活性な化合物を:
a)対象とするタンパク質の活性を変化させる少なくとも1個のペプチドを選択し、そして
b)選択したペプチドの少なくとも1つのアミノ酸配列に共有結合された少なくとも1つのビヒクルを含む薬理学的物質を調製する
ことを含む方法によって調製する。好ましいビヒクルはFcドメインである。ステップ(a)でスクリーニングしたペプチドを、好ましくはファージディスプレイライブラリーにおいて発現させる。ビヒクルとペプチドは、下記でさらに述べるように、ペプチド又はビヒクルのN又はC末端を通して結合しうる。上記化合物の誘導体(下記に述べる)も本発明に包含される。
図1は、本発明の例示的方法の概要図を示す。この好ましい方法では、ビヒクルはFcドメインであり、それがFcドメインとペプチドの両方をコードするDNA構築物からの発現によってペプチドに共有結合する。図1に示すように、Fcドメインはこの方法において自発的に二量体を形成する。
A、D:一重ジスルフィド結合二量体。IgG1抗体は、典型的には定常領域と可変領域の間のちょうつがい部位に2個のジスルフィド結合を持つ。図2Aと2DにおけるFcドメインは、2個のジスルフィド結合部位間の切断によって、若しくは非反応性残基(例えばアラニル)によるシステイニル残基の置換によって形成されうる。図2AではFcドメインはペプチドのアミノ末端で結合しており、2Dではカルボキシル末端で結合している。
TMP:アミノ酸配列、IEGPTLRQWLAARA(配列番号13)を持つTPO擬似ペプチド、
TMP−TMP:アミノ酸配列、IEGPTLRQWLAARA−GGGGGGGG−IEGPTLRQWLAARA(配列番号14)を持つTPO擬似ペプチド、
PEG−TMP−TMP:PEG基が図6に示すような平均分子量5kDのPEGである、配列番号14のペプチド、
Fc−TMP−TMP:同一の第二モノマーで二量体化された(すなわち、図2に示すように、Cys残基7と10が第二モノマー中の対応するCys残基に結合して二量体を形成する)配列番号8(図8)の化合物、そして
TMP−TMP−Fcは、FcドメインがTMP−TMPペプチドのN末端ではなくC末端で結合していることを除いて、TMP−TMP−Fcと同じように二量体化された配列番号10(図9)の化合物である。
EMP−Fcは、FcドメインがEMPペプチドのN末端ではなくC末端で結合していることを除いて、Fc−EMPと同じように二量体化された配列番号18(図14)の化合物。
用語の定義
この明細書を通じて使用される用語は、特定の場合に限って異なる記載がないかぎり、下記のように定義される。
全般。本発明に従って製造される物質の組成物においては、ペプチドのN末端又はC末端を通してペプチドをビヒクルに連結することができる。従って、本発明のビヒクル−ペプチド分子は次の式I:
(X1)a−F1(X2)b
[式中、F1はビヒクル(好ましくはFcドメイン)であり、
X1及びX2は、各々独立に−(L1)c−P1、−(L1)c−P1−(L2)d−P2、−(L1)c−P1−(L2)d−P2−(L3)e−P3、及び−(L1)c−P1−(L2)d−P2−(L3)e−P3−(L4)f−P4から選択され、
P1、P2、P3及びP4は各々独立に薬理学的に活性なペプチドの配列であり、
L1、L2、L3及びL4は各々独立にリンカーであり、そして
a、b、c、d、e及びfは、aとbの少なくとも一方が1であることを条件として、各々独立に0又は1である]
によって表わすことができる。
X1−F1
及びそのマルチマー[式中、F1はFcドメインであり、X1のC末端で結合している]、式III:
F1−X2
及びそのマルチマー[式中、F1はFcドメインであり、X2のN末端で結合している]、式IV:
F1−(L1)c−P1
及びそのマルチマー[式中、F1はFcドメインであり、−(L1)c−P1のN末端で結合している]、式V
F1−(L1)c−P1−(L2)d−P2
及びそのマルチマー[式中、F1はFcドメインであり、−L1−P1−L2−P2のN末端で結合している]
の好ましい化合物を含む。
・ペプチドがVEGF擬似又はVEGF受容体拮抗物質、HER2作用物質又は拮抗物質、CD20拮抗物質等である場合には、癌、
・対象とするタンパク質がCKR3拮抗物質、IL−5受容体拮抗物質等である場合には、喘息、
・対象とするタンパク質がGPIIb拮抗物質、GPIIIa拮抗物質等である場合には、血栓症、
・対象とするタンパク質がIL−2受容体拮抗物質、CD40作用物質又は拮抗物質、CD40L作用物質又は拮抗物質、サイモポイエチン擬似等である場合には、自己免疫疾患及び免疫調節に関わる他の状態。
1.ジスルフィド結合の形成に関わる部位が除去されている。そのような除去は、本発明の分子を生成するために使用する宿主細胞中に存在する他のシステイン含有タンパク質との反応を回避することができる。このために、N末端のシステイン含有セグメントを切断するか、若しくはシステイン残基を欠失させる又は他のアミノ酸(例えばアラニル、セリル)で置換することができる。特に、配列番号2のN末端の20アミノ酸セグメントを切断する、若しくは配列番号2の7及び10位のシステイン残基を欠失させる又は置換することができる。システイン残基を除去したときでも、一本鎖Fcドメインはまだ、非共有結合で結ばれた二量体Fcドメインを形成することができる。
2.選択した宿主細胞とより適合性にするために天然Fcが修飾されている。例えば、プロリンイミノペプチダーゼのような大腸菌の消化酵素によって認識されうる、典型的天然FcのN末端近くのPA配列を除去することができる。また、特に分子が大腸菌のような細菌細胞において組換え発現されるときには、N末端のメチオニン残基を付加することもできる。配列番号2のFcドメイン(図4)はそのようなFc変異体の1つである。
3.選択した宿主細胞において発現されたときのN末端の異質性を防ぐために、天然FcのN末端の一部が除去されている。このために、N末端の最初の20個のアミノ酸残基のいずれか、特に1、2、3、4及び5位のアミノ酸残基を欠失させることができる。
4.1つ又はそれ以上のグリコシル化部位が除去されている。典型的には、グリコシル化されている残基(例えばアスパラギン)は細胞溶解反応をもたらすと考えられる。そのような残基を欠失させる又はグリコシル化されていない残基(例えばアラニン)で置換することができる。
5.C1q結合部位のような補体との相互作用に関わる部位が除去されている。例えば、ヒトIgG1のEKK配列を欠失させる又は置換することができる。補体の集積は本発明の分子にとって有利ではないと考えられ、それ故かかるFc変異体によって回避することができる。
6.サルベージ受容体以外のFc受容体への結合に影響を及ぼす部位が除去されている。天然Fcは、本発明の融合分子にとって必要ではない特定の白血球と相互作用するための部位を持つと考えられ、それ故かかる部位を除去することができる。
7.ADCC部位が除去されている。ADCC部位は当技術分野において既知である;IgG1のADCC部位に関しては、例えばMolec.Immunol.29(5):633−9(1992)参照。これらの部位も本発明の融合分子には必要なく、従って除去されうる。
8.天然Fcがヒト以外の抗体から誘導されるときには、天然Fcをヒト化することができる。典型的には、天然Fcをヒト化するために、ヒト以外の天然Fc中の選択した残基をヒト天然Fcにおいて通常認められる残基で置換する。抗体のヒト化のための手法は当技術において周知である。
(Gly)3Lys(Gly)4(配列番号333)、
(Gly)3AsnGlySer(Gly)2(配列番号334)、
(Gly)3Cys(Gly)4(配列番号335)、及び
GlyProAsnGlyGly(配列番号336)。
上記の表記法を説明すると、例えば、(Gly)3Lys(Gly)4はGly−Gly−Gly−Lys−Gly−Gly−Gly−Glyを意味する。GlyとAlaの組合せも好ましい。ここに示すリンカーは例示である;本発明の範囲内のリンカーははるかに長い場合もあり、また他の残基を含みうる。
である。ペプチドリンカーは、上述したのと同じようにして誘導体を形成するように改変することができる。
1.化合物又はその一部が環状である。例えばペプチド部分が、ジスルフィド結合の形成によって環化しうる2個又はそれ以上のCys残基を含む(例えばリンカー中に)ように修飾することができる。環化誘導体の調製に関する参考文献の引用については表2参照。
本発明の化合物は、主として組換えDNA手法を用いて形質転換宿主細胞において作製されうる。そのために、当該ペプチドをコードする組換えDNA分子を調製する。そのようなDNA分子を調製する方法は当技術において周知である。例えば、適当な制限酵素を使用して当該ペプチドをコードする配列をDNAから切り出すことができる。その代わりには、ホスホルアミデート(phosphoramidate)法のような化学合成手法を用いてDNA分子を合成することができる。また、これらの手法の組合せも使用できる。
概説。本発明の化合物は、対象とするタンパク質の作用物質、擬似又は拮抗物質としてかかる対象タンパク質に結合するそれらの能力から生じる薬理学的活性を持つ。特定化合物の有用性を表2に示す。これらの化合物の活性は、当技術において既知のアッセイによって測定することができる。TPO擬似及びEPO擬似化合物に関しては、本文中の実施例の章でさらに説明する。
概説。本発明はまた、本発明の化合物の製薬組成物を使用する方法を提供する。そのような製薬組成物は、注入による投与、経口、肺、経鼻、経皮又は他の形態の投与用でありうる。一般に、本発明は、製薬上許容される希釈剤、防腐剤、溶解補助剤、乳化剤、アジュバント及び/又はキャリアと共に本発明の化合物の有効量を含む製薬組成物を包含する。そのような組成物は、様々な緩衝剤含量(例えばTris−HCl、酢酸塩、リン酸塩)、pH及びイオン強度の希釈剤、界面活性剤及び溶解補助剤(例えばTween 80、Polysorbate 80)のような添加物、抗酸化剤(例えばアスコルビン酸、メタ重亜硫酸ナトリウム)、防腐剤(例えばThimersol、ベンジルアルコール)及び充填剤(例えばラクトース、マンニトール)、ポリ乳酸、ポリグリコール酸等のようなポリマー化合物の微粒子製剤又はリポソームへの物質の組込みを含む。ヒアルロン酸も使用でき、これは循環中に存在する時間の延長を促進する作用を持つと考えられる。そのような組成物は、本発明のタンパク質及び誘導体の物理的状態、安定性、インビボでの放出速度、及びインビボでのクリアランス速度に影響を及ぼしうる。例えば、参照してここに組込まれる、レミントンの製薬化学(Remington’s Pharmaceutical Sciences、第18版(1990,Mack Publishing Co.,Easton,PA18042)p.1435−1712参照。当該組成物は液体形態、若しくは凍結乾燥形態のような乾燥粉末で調製することができる。経皮製剤と同様に、移植可能な持続放出性製剤も考慮される。
そのすべてが当業者には熟知のものである、ネブライザ、定量吸入器、及び粉末吸入器を含むがこれらに限定されない、治療薬剤の肺送達用に設計された広い範囲の機械的装置が、本発明を実施する際の使用に関して考慮される。本発明の実施に適した市販の装置のいくつかの特定例は、Mallinckrodt,Inc.,St.Louis,Missouriが製造しているUltravioletネブライザ、Marquest Medical Products,Englewood,Coloradoが製造しているAcorn IIネブライザ、Glaxo Inc.,Research Triangle Park,North Carolinaが製造しているVentolin定量吸入器、及びFisons Corp.,Bedford,Massachusettsが製造しているSpinhaler粉末吸入器である。
発明者は多くの異なる種類の活性を有する分子の好ましいペプチド配列を決定した。発明者はさらに、好ましいリンカーおよびビヒクルと結合するこれらの好ましいペプチドの好ましい構造を決定した。これらの好ましいペプチドの好ましい構造を以下の表21に列挙する。
前記の化合物を以下に記載するように調製できる。これらの実施例は本発明の好ましい態様を含んでなり、本発明を説明するが、これを限定するものではない。
TPO−擬似物質
以下の実施例では本明細書に後記する表Aに示す数字で同定されたペプチドを使用する。
ペプチド17b(12mg)およびMeO−PEG−SH5000(30mg、2当量)を水性緩衝液(pH8)1mlに溶解した。混合物を室温で約30分インキュベートし、分析用HPLCにより反応を確認し、>80%の反応が完了したことが示された。調製用HPLCによりPEG化物質を単離した。
ペプチド18(14mg)およびMeO−PEGマレイミド(25mg)を水性緩衝液(pH8)約1.5mlに溶解した。混合物を室温で約30分間インキュベートし、そのときサンプルのアリコートをHPLCカラムに供して分析用HPLCでモニター観察し、約70%の形質転換が完了していた。調製用HPLCによりPEG化物質を精製した。
TPOインビトロ生物検定はヒトmpl受容体でトランスフェクトしたマウス32D細胞のIL−3依存性クローンを利用する細胞分裂誘起検定である。この検定に関してはWO95/26746により詳細に記載されている。細胞を10%胎児クローンIIおよび1ng/ml mIL−3を含有するMEM培地中に保持する。サンプルを添加する前にmIL−3不含成長培地で2回すすいで細胞を調製する。拡張12点TPO検量線を作成し、33ないし39pg/mlの範囲になる。各サンプルに関して4希釈(検量線の直線部分内に入ると推測される、100ないし125pg/ml)を調製し、三重に実施する。10000セル/ウェルを含有する96ウェル・マイクロタイタープレートの適当なウェルに100μlの容量のサンプルの各希釈物または標準物質を加える。37℃および10% CO2で44時間後、MTS(細胞によりホルマザンに生物還元されるテトラゾリウム化合物)を各ウェルに加える。約6時間後、プレート・リーダーで490nmにおける光学密度を読み取る。用量依存性曲線(logTPO濃度対O.D.バックグランド)を作成し、検量線の直線部分に入る点の直線回帰分析を行う。得られた直線の方程式および希釈因子の補正を用いて未知の試験サンプルの濃度を決定する。
連続して連結するTMP反復の設計は、c−Mpl(TPO受容体)と効果的に相互作用するためにTMPの二量体形態が要求され、受容体との関係においてそれらが互いにどのように巻きついているかに依存して、全体的な二量体立体配座を乱さないように2個のTMP分子がCからN末端への立体配置で一緒につなぎとめられているという仮定に基づいている。明らかに、縦列連結した反復の設計の成功は、2個の連続し、整列したTMP単量体のCおよびN末端に結合するリンカーの長さおよび組成の適切な選別に依存するものである。c−Mplに結合するTMPの構造に関する情報を利用できないので、0ないし10および14個のグリシン残基(表A)からなるリンカーを有する一連の反復ペプチドを合成した。融通性のあるポリグリシンペプチド鎖により2個のつなぎとめられたTMP反復の自由な折りたたみが可能になり、要求される立体配座にでき、一方その他のアミノ酸配列は、その剛性により受容体との関係において反復ペプチドの正常なパッキングが崩壊する望ましくない二次構造をとるという理論に基づいて、平易性および融通性の故にグリシンを選択した。
この最初の一連のTMP縦列反復に続いて、異なるリンカーと共にかまたは単量体そのもの中に修飾を含んでいくつかのその他の分子を設計した。これらの分子の第1のものはペプチド13であり、βターン型2次構造を形成する傾向が高いことで知られている配列であるGPNGから成るリンカーを有する。単量体よりも約100倍以上強力であるが、このペプチドは等価のGGGG連結アナログよりも>10倍以下の活性であることが見出されている。このように、比較的堅固なβターンをリンカー領域で導入することにより、この短いリンカー形態において最適な作用物質立体配座にわずかな歪を生じるようである。
MGDFがhGHに類似の方法で作用する、すなわち活性化のためにタンパク質リガンドの1個の分子が受容体の2個の分子に結合することは周知である。Wellsら、Ann.Rev.Biochem.65:609−34(1996)。現在、この相互作用はもっと小さいペプチドであるTMPの作用により擬似される。しかしながら、本研究は、C−C平行またはC−N連続のいずれかの様式のTMPの共有結合性二量体形成が103以上の因子で元来の単量体のインビトロ生物学的能力を増強するので、この擬似が2個のTMP分子の協奏作用を要求することを示唆している。単量体の生物学的能力が相対的に低いのは恐らく非共有結合性二量体の形成の効率が悪いためである。あらかじめ形成された共有結合性反復は非共有結合性二量体形成のためにエントロピーバリヤを排除する能力を有し、これは小型の14−残基ペプチドの2個の分子間の弱い非共有結合性相互作用により排他的にもたらされる。
Fc−TMP融合
ヒトIgG1のFc領域とのN末端かまたはC末端のいずれかの融合体として単量体または二量体のいずれかの形態でTMP(および実施例3に記載のEMP)を発現した。全ての場合においてケースで発現ベクターpAMG21にてluxPRプロモーター・プロモーターを用いて発現を構築した。
TPO擬似ペプチドの単量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を標準的なPCR技術を用いて構築した。PCR反応の鋳型はpFc−A3ベクターおよび合成TMP遺伝子であった。合成遺伝子を以下に示す3個の重複オリゴヌクレオチドから構築し(各々配列番号364、365および366):
標準的なPCR技術を用いてTPO擬似ペプチドの二量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を構築した。PCR反応の鋳型はpFc−A3ベクターおよび合成TMP−TMP遺伝子であった。4個の重複オリゴヌクレオチドから合成遺伝子を構築し(各々配列番号371ないし374)以下に示す:
TMP−TMP−Fc
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したTPO擬似ペプチドの縦列反復をコードするDNA配列を構築した。PCR反応の鋳型は#3688株のEMP−Fcプラスミド(実施例3を参照のこと)およびTMP二量体をコードする合成遺伝子であった。7個の重複オリゴヌクレオチドから縦列反復の合成遺伝子を構築し(各々配列番号377ないし383)以下に示す:
TMP−Fc
ヒトIgG1のFc領域にイン・フレーム融合したTPO擬似ペプチドの単量体をコードするDNA配列を偶然にもTMP−TMP−Fcのライゲーションで得たが、これは恐らくプライマー1885−54が1885−53および1885−58にアニリーリングする能力によるものであろう。TMP−Fc構築物に関して正確なヌクレオチド配列を有する1個のクローンを選別し、アムゲン#3788株と称した。
大腸菌GM221におけるpAMG21−Fc融合構築物の各々の培養物を50mg/mlカナマイシン含有ルリア・ブロス培地中37℃で成長させた。合成オートインデューサーN−(3−オクソヘキサノイル)−DL−ホモセリン・ラクトンを培養培地に添加し、最終濃度20ng/mlにして、luxPRプロモーターからの遺伝子生成物の発現を誘導した。培養物を37℃でさらに3時間インキュベートした。3時間後、封入体の存在に関して細菌培養物を顕微鏡で試験し、次いで遠心により収集した。誘導した培養物中光屈折性の封入体が観察され、これはFc融合体が大腸菌の不溶性分画においてほとんど生成されていることを示している。10%β−メルカプトエタノールを含有するラエムリ・サンプル緩衝液に細胞ペレットを再懸濁することにより直接的に溶解し、SDS−PAGEにより分析した。各々の場合、SDS−PAGEゲルに適当な分子量のクーマシー染色の強いバンドが観察された。
発現プラスミドpAMG21はアムゲン発現ベクターpCFM1656(ATCC#69576)から誘導でき、これもまた米国特許第4710473号に記載のアムゲン発現ベクター系から誘導した。pCFM1656プラスミドは:
(a)T4ポリメラーゼ酵素で末端を埋め、次いで平滑末端ライゲーションを行うことにより、2個の内在するNdeI制限部位を崩壊させること;
(b)合成PLプロモーターを含有する独自のAatIIおよびClaI制限部位間のDNA配列を、PLプロモーターを含有するpCFM636(特許番号第4710473号)から得られた類似のフラグメント(以下の配列番号386を参照のこと)と置き換えること;および
(c)独自のClaIおよびKpnI制限部位間の小型のDNA配列を配列番号388の配列を有するオリゴヌクレオチドと置換すること;
により記載したpCFM836プラスミド(特許番号第4710473号)から誘導できる。
アムゲン#2596宿主株はアムゲン#393株から誘導した大腸菌K12株である。これを修飾し、初期ebg領域に温度感受性ラムダレプレッサーcI857s7、後期ebg領域にlacIQレプレッサーの両方を含むようにした(68分)。これらの2個のレプレッサー遺伝子の存在によりこの宿主が種々の発現系と共に使用できるようになるが、しかしながらこれらの両方のレプレッサーはluxPRからの発現には適切ではない。形質転換されなかった宿主は抗生物質抵抗性がない。
誘導前に大腸菌GM221のpAMG21−Fc−TMP−TMPの培養物を50μg/mlカナマイシン含有ルリア・ブロス培地中37℃でインキュベートした。最終濃度20ng/mlになるように培養培地に合成オートインデューサーN−(3−オクソヘキサノイル)−DL−ホモセリン・ラクトンを添加することによりluxPRプロモーターからFc−TMP−TMP遺伝子生成物発現を誘導し、培養物を37℃でさらに3時間インキュベートした。3時間後、封入体の存在に関して細菌培養物を顕微鏡で試験し、次いで遠心により収集した。誘導した培養物中光屈折性の封入体が観察され、これはFc−TMP−TMPが大腸菌の不溶性分画においてほとんどが生成されていることを示している。10%β−メルカプトエタノールを含有するラエムリ・サンプル緩衝液に再懸濁することにより細胞ペレットを直接的に溶解し、SDS−PAGEにより分析した。SDS−PAGEゲルにおよそ30kDaのクーマシー染色の強いバンドが観察された。予測される遺伝子生成物は269個のアミノ酸の長さであり、予測される分子量は約29.5kDaである。また10lのスケールで標準バッチ条件下発酵をも行い、ベンチスケールで得られた発現レベルに類似したFc−TMP−TMPの発現レベルが得られた。
高圧ホモジナイゼーション(14000PSIで2パス)により水中(1/10)で細胞を破壊し、遠心(J−6Bで4200RPMで1時間)により封入体を回収した。6M グアニジン、50mM トリス、8mM DTT(pH8.7)中1時間1/10の比率で封入体を可溶化する。可溶化した混合物を2M 尿素、50mM トリス、160mM アルギニン、3mM システイン(pH8.5)で20倍希釈する。混合物を一晩冷却して攪拌し、次いで限外濾過により約10倍に濃縮する。次いで10mM トリス、1.5M 尿素(pH9)で3倍希釈する。次いでこの混合物のpHを酢酸でpH5に調整する。沈殿物を遠心により除去し、20mM NaAc、100mM NaCl(pH5)で平衡にしたSP−セファロース・ファスト・フロー・カラムに上澄を装填する(10mg/ml タンパク質装填、室温)。100mM NaClないし500mM NaClの範囲の同一緩衝液の20カラム容量グラジエントを用いてタンパク質を溶出する。カラムからのプールを3倍希釈し、20mM NaAc、150mM NaCl(pH5)で平衡にしたSP−セファロースHPカラムに装填する(10mg/ml タンパク質装填、室温)。150mM NaClないし400mM NaClの範囲の同一緩衝液の20カラム容量グラジエントを用いてタンパク質を溶出する。ピークをプールし、濾過する。
以下は本発明の種々化合物を用いたマウスにおけるインビボデータの要旨である。
Fc−EMP融合
Fc−EMP
標準PCR技術を用いてEPO擬似ペプチドの単量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を構築した。PCR反応の鋳型はFc配列(pFc−A3、1997年7月3日公開の国際出願WO97/23614に記載)を含有するベクターおよびEPO単量体をコードする合成遺伝子であった。単量体の合成遺伝子は以下に示す4個の重複オリゴヌクレオチド(各々配列番号390ないし393)から構築した:
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したEPO擬似ペプチドの単量体をコードするDNA配列を構築した。PCR反応の鋳型はpFc−A3aベクターおよびEPO単量体をコードする合成遺伝子であった。4個の重複オリゴヌクレオチド1798−4および1798−5(前記)並びに1798−6および1798−7(各々配列番号400および401)から以下に示す単量体の合成遺伝子を構築した:
EMP−EMP−Fc
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したEPO擬似ペプチドの二量体をコードするDNA配列を構築した。PCR反応の鋳型は前記の#3688株のEMP−FcプラスミドおよびEPO二量体をコードする合成遺伝子であった。8個の重複オリゴヌクレオチドから以下に示す二量体の合成遺伝子を構築した(各々配列番号408ないし415):
標準的なPCR技術を用いてEPO擬似ペプチドの二量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を構築した。PCR反応の鋳型は前記の3688および3813株からのプラスミドであった。
インビボでの特徴づけは以下のとおり実施した。
TNF−α阻害因子
Fc−TNF−α阻害因子
標準的なPCR技術を用いてTNF−α阻害因子の単量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を構築した。センスプライマー1216−52およびアンチセンスプライマー2295−89(各々配列番号1112および1113)を用いてFc−EMP融合#3718株(実施例3を参照のこと)のDNAとのPCR反応で分子のFcおよび5グリシンリンカー部分を作った。以下に示すPCRプライマー2295−89によりTNF−α阻害ペプチドをコードするヌクレオチドが提供される:
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したTNF−α阻害ペプチドをコードするDNA配列を構築した。PCR反応の鋳型は5個のグリシンリンカーを介してFcに融合した関連性のないペプチドを含有するプラスミドであった。アンチセンスプライマーとして提供されるプライマー1200−54とセンスPCRプライマー2295−88(各々配列番号1117および407)によりTNF−α阻害ペプチドをコードするヌクレオチドが提供された。プライマー配列を以下に示す:
大腸菌GM221のpAMG21−Fc融合構築物の各々の培養物を50mg/mlカナマイシン含有ルリア・ブロス培地中37℃でインキュベートした。最終濃度20ng/mlで培養培地に合成オートインデューサーN−(3−オクソヘキサノイル)−DL−ホモセリン・ラクトンを添加することによりluxPRプロモーターから遺伝子生成物の発現を誘導した。培養物を37℃でさらに3時間インキュベートした。3時間後、封入体の存在に関して細菌培養物を顕微鏡で試験し、次いで遠心により収集した。誘導した培養物中光屈折性の封入体が観察され、これはFc融合体が大腸菌の不溶性分画においてほとんどが生成されていることを示している。10%β−メルカプトエタノールを含有するラエムリ・サンプル緩衝液に再懸濁することにより細胞ペレットを直接的に溶解し、SDS−PAGEにより分析した。各々の場合でSDS−PAGEゲルに適当な分子量のクーマシー染色の強いバンドが観察された。
高圧ホモジナイゼーション(14000PSIで2パス)により水中(1/10)で細胞を破壊し、遠心(J−6Bで4200RPMで1時間)により封入体を回収した。6M グアニジン、50mM トリス、8mM DTT(pH8.7)中1時間1/10の比率で封入体を可溶化する。可溶化した混合物を2M 尿素、50mM トリス、160mM アルギニン、3mM システイン(pH8.5)で20倍希釈する。混合物を一晩冷却して攪拌し、次いで限外濾過により約10倍に濃縮する。次いで10mM トリス、1.5M 尿素(pH9)で3倍希釈する。次いでこの混合物のpHを酢酸でpH5に調整する。沈殿物を遠心により除去し、20mM NaAc、100mM NaCl(pH5)で平衡にしたSP−セファロース・ファスト・フロー・カラムに上澄を装填する(10mg/ml タンパク質装填、室温)。100mM NaClないし500mM NaClの範囲の同一緩衝液の20カラム容量グラジエントを用いてカラムからタンパク質を溶出する。カラムからのプールを3倍希釈し、20mM NaAc、150mM NaCl(pH5)で平衡にしたSP−セファロースHPカラムに装填する(10mg/ml タンパク質装填、室温)。150mM NaClないし400mM NaClの範囲の同一緩衝液の20カラム容量グラジエントを用いてタンパク質を溶出する。ピークをプールし、濾過する。
本明細書の教示を熟知する当業者に可能な方法によりBIAコアによりこれらのペプチド融合タンパク質のTNF−αへの結合を特徴付けできる。
IL−1拮抗物質
Fc−IL−1拮抗物質
標準的なPCR技術を用いてIL−1拮抗物質ペプチドの単量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を構築した。センスプライマー1216−52およびアンチセンスプライマー2269−70(各々配列番号1112および1118)を用いてFc−EMP融合#3718株(実施例3を参照のこと)のDNAとのPCR反応で分子のFcおよび5グリシンリンカー部分を作った。以下に示すPCRプライマー2269−70によりIL−1拮抗物質ペプチドをコードするヌクレオチドが提供される:
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したIL−1拮抗物質ペプチドをコードするDNA配列を構築した。PCR反応の鋳型は5個のグリシンリンカーを介してFcに融合した関連性のないペプチドを含有するプラスミドであった。アンチセンスプライマーとして提供されるプライマー1200−54とセンスPCRプライマー2269−69により(各々配列番号1119および407)IL−1拮抗物質ペプチドをコードするヌクレオチドが提供された。プライマー配列を以下に示す:
IGEN系を用いてIL−1β、Il−1RAおよびFc−結合IL−1ペプチド配列間のIL−1受容体結合競合検定を実施した。反応物は0.4nMビオチン−IL−1R+15nM IL−1−TAG+3μM コペティター+20μg/mlストレプトビジン結合ビーズを含有し、ここでコンペティターはIL−1RA、Fc−IL−1拮抗物質、IL−1拮抗物質−Fcである。コンペティター濃度3μMないし1.5pMの範囲で競合を検定した。結果を以下の表Cに示す:
VEGF−拮抗物質
Fc−VEGF拮抗物質
標準的なPCR技術を用いてVEGF擬似ペプチドの単量体にイン・フレーム融合したヒトIgG1のFc領域をコードする配列を構築した。PCR反応の鋳型はpFc−A3プラスミドおよび合成VEGF擬似ペプチド遺伝子であった。以下の2個のオリゴヌクレオチドプライマー(各々配列番号1120および1121)をアニーリングして合成遺伝子の集合体を形成した:
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したVEGF擬似ペプチドをコードするDNA配列を構築した。PCR反応の鋳型はpFc−A3プラスミドおよび前記の合成VEGF擬似ペプチド遺伝子であった。センスおよびアンチセンスプライマーとして2293−07および2293−08(各々配列番号1127および1128)を用いてPCR反応で合成二本鎖を増幅した。
MMP阻害因子
Fc−MMP阻害因子
標準的なPCR技術を用いてMMP阻害ペプチドの単量体にイン・フレーム融合したヒトIgG1のFc領域をコードするDNA配列を構築した。センスプライマー1216−52およびアンチセンスプライマー2308−67(各々配列番号1112および1131)を用いてFc−TNF−α阻害因子融合株#4544(実施例4を参照のこと)からのDNAとのPCR反応で分子のFcおよび5グシリンリンカー部分を作った。MMP阻害因子ペプチドをコードするヌクレオチドはPCRプライマー2308−67により提供され、以下に示す:
標準的なPCR技術を用いてヒトIgG1のFc領域にイン・フレーム融合したMMP阻害ペプチドをコードするDNA配列を構築した。Fc−TNF−α阻害因子融合株#4543(実施例4を参照のこと)からのDNAとのPCR反応で分子のFcおよび5グシリンリンカー部分を作った。MMP阻害ペプチドをコードするヌクレオチドはアンチセンスプライマーとして供されるプライマー1200−54とセンスPCRプライマー2308−66により提供された。プライマー配列は以下に示す:
本明細書において使用した略語を特記しない限り以下のように定義する。
Ac:アセチル(アセチル化残基に関して使用)
AcBpa:アセチル化p−ベンゾイル−L−フェニルアラニン
ADCC:抗体依存性細胞毒性
Aib:アミノイソブチル酸
βA:ベータ・アラニン
Bpa:p−ベンゾイル−L−フェニルアラニン
BrAc:ブロモアセチル(BrCH2C(O))
BSA:ウシ血清アルブミン
Bzl:ベンジル
Cap:カプロン酸
CTL:細胞毒性Tリンパ球
CTLA4:細胞毒性Tリンパ球抗原4
DARC:ダッフィ式血液型抗原受容体
DCC:ジシルコヘキシルカルボジイミド
Dde:1−(4,4−ジメチル−2,6−ジオクソ−シクロヘキシルジエン)エチル
EMP:エリトロポエチン擬似ペプチド
ESI−MS:電子スプレイイオン化質量分析法
EPO:エリトロポエチン
Fmoc:フルオレニルメトキシカルボニル
G−CSF:顆粒球コロニー刺激因子
GH:成長ホルモン
HCT:ヘマトクリット
HGB:ヘモグロビン
hGH:ヒト成長ホルモン
HOBt:1−ヒドロキシベンゾトリアゾール
HPLC:高速液体クロマトグラフィー
IL:インターロイキン
IL−R:インターロイキン受容体
IL−1R:インターロイキン−1受容体
IL−1ra:インターロイキン−1受容体拮抗物質
Lau:ラウリン酸
LPS:リポ多糖類
LYMPH:リンパ球
MALDI−MS:行列補助レーザー脱離イオン化質量分析法
Me:メチル
MeO:メトキシ
MHC:主要組織適合複合体
MMP:マトリックス・メタロプロテイナーゼ
MMPI:マトリックス・メタロプロテイナーゼ・阻害因子
1−Nap:1−ナフチルアラニン
NEUT:好中球
NGF:神経成長因子
Nle:ノルロイシン
NMP:N−メチル−2−ピロリジノン
PAGE:ポリアクリルアミドゲル電気泳動
PBS:リン酸緩衝生理食塩水
Pbf:2,2,4,6,7−ペンダメチルジヒドロベンゾフラン−5−スルフォニル
PCR:ポリメラーゼ連鎖反応
Pec:ピペコリン酸
PEG:ポリ(エチレングリコール)
pGlu:ピログルタミン酸
Pic:ピコリン酸
PLT:血小板
pY:ホスフォチロシン
RBC:赤血球
RBS:リボソーム結合部位
RT:室温(25℃)
Sar:サルコシン
SDS:ドデシル硫酸ナトリウム
STK:セリン−スレオニン・キナーゼ
t−Boc:ターシャリー・ブトキシカルボニル
tBu:ターシャリー・ブチル
TGF:組織成長因子
THF:胸腺液性因子
TK:チロシン・キナーゼ
TMP:トロンボポエチン擬似ペプチド
TNF:組織壊死因子
TPO:トロンボポエチン
TRAIL:TNF関連アポトシス誘起リガンド
Trt:トリチル
UK:ウロキナーゼ
UKR:ウロキナーゼ受容体
VEGF:血管内皮細胞成長因子
VIP:血管作用性小腸ペプチド
WBC:白血球
Claims (11)
- 式:
(X1)a−F1−(X2)b
[式中、F1はFcドメインであり、
X1及びX2は、各々独立に−(L1)c−P1、−(L1)c−P1−(L2)d−P2、−(L1)c−P1−(L2)d−P2−(L3)e−P3、及び−(L1)c−P1−(L2)d−P2−(L3)e−P3−(L4)f−P4から選択され、
P1、P2、P3及びP4は各々独立にランダム化されたEPO擬似ペプチドの配列であり、
L1、L2、L3及びL4は各々独立にリンカーであり、そして
a、b、c、d、e及びfは、aとbの少なくとも一方が1であることを条件として、各々独立に0又は1であり、ペプチドは2〜40アミノ酸の分子を指し、X1もX2も天然タンパク質ではない]
の物質及びその多量体の組成物。 - 式:
X1−F1
又は
F1−X2
の請求項1に記載の物質の組成物。 - 式:
F1−(L1)c−P1
の請求項1に記載の物質の組成物。 - 式:
F1−(L1)c−P1−(L2)d−P2
の請求項1に記載の物質の組成物。 - F1がIgG Fcドメインである、請求項1に記載の物質の組成物。
- F1がIgG1 Fcドメインである、請求項1に記載の物質の組成物。
- F1が配列番号2の配列を含む、請求項1に記載の物質の組成物。
- EPO擬似ペプチド配列が表5から選択される、請求項1に記載の物質の組成物。
- F1が配列番号2の配列を含む、請求項8に記載の物質の組成物。
- 配列番号83、84、85、124、419、420、421及び461から選択される配列を含む、請求項1に記載の物質の組成物。
- 配列番号339及び340から選択される配列を含む、請求項1に記載の物質の組成物。
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JP2006288382A Pending JP2007089586A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288324A Withdrawn JP2007091746A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288398A Pending JP2007105044A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288346A Pending JP2007084556A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288325A Withdrawn JP2007084555A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288347A Pending JP2007091747A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288383A Withdrawn JP2007084557A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
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JP2006288382A Pending JP2007089586A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288324A Withdrawn JP2007091746A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288398A Pending JP2007105044A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
JP2006288346A Pending JP2007084556A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
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JP2006288397A Withdrawn JP2007084558A (ja) | 1998-10-23 | 2006-10-24 | 治療薬としての修飾ペプチド |
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US5349053A (en) * | 1990-06-01 | 1994-09-20 | Protein Design Labs, Inc. | Chimeric ligand/immunoglobulin molecules and their uses |
WO1998024477A1 (en) * | 1996-12-06 | 1998-06-11 | Amgen Inc. | Combination therapy using an il-1 inhibitor for treating il-1 mediated diseases |
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